The diagnosis of schizophrenia presently relies on essentially the same methods of clinical interviewing, symptom identification, and application of diagnostic criteria that have been in use for nearly 25 years. Given the considerable genetic contribution toward the etiology of schizophrenia, a biologically based set of diagnostic markers may be more efficient for validating the diagnosis and its subtypes, and for improving diagnostic sensitivity and specificity. Moreover, if diagnostic markers can be identified in peripheral blood rather than in postmortem brain tissue, the promise of early identification and improved treatment might be realized. As a first step toward establishing such biologically based markers, the main objective of this project is to identify and validate highly reliable and specific patterns of gene expression in peripheral blood cells that differentiate patients with schizophrenia from control subjects. We have generated pilot data identifying differences in gene expression profiles between patients with schizophrenia, patients with bipolar disorder, and control subjects; in the proposed project, novel applications of oligonucleotide microarrays and advanced statistical techniques will be used to extend and validate these preliminary findings. To accomplish this, we propose the following specific aims: 1) Quantify gene expression levels in peripheral lymphocytes from patients with schizophrenia and control subjects; 2) Quantify levels of gene expression induced by the application of typical and atypical antipsychotic medications to cultured lymphocytes obtained from control subjects, in order to rule out candidate biomarker genes that respond to medication but are not specific to the disease process; 3) Prioritize candidate genes for subsequent verification and validation as disease biomarkers using novel data-analytic and statistical methods that control the rate of inferential errors; 4) Verify the differential expression of top candidate genes in peripheral lymphocytes by more precise mRNA quantification techniques; and 5) Validate the differential expression of top candidate genes in postmortem brain tissue obtained from patients with schizophrenia and control subjects. Long-term goals (beyond this proposal) will be to replicate and extend our findings, test for other potential confounders of peripheral bloodbased gene expression profiling, and test for specificity vis-a-vis psychiatric comparison groups. Ultimately, biologically based diagnostic markers may substantially enhance the possibilities for early identification, intervention, and prevention, and also facilitate the identification of etiologic factors in the illness.